References

1. Von Rosenvinge EC, Raufman J-P. Gastrointestinal peptides and regulation of gastric acid secretion.

Curr Opin Endocrinol Diabetes Obes 2010;17(1):40–44.

2. Schubert M, Peura D. Control of gastric acid secretion in health and disease. Gastroenterology

2008;134(7):1842–1860.

3. Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2008;24:(6)659–664.

4. Debas HT, Carvajal SH. Vagal regulation of acid secretion and gastrin release. Yale J Biol Med

1994;67:145–151.

5. Cover TL. Role of Heliocobacter pylori CagL in modulating gastrin expression. Gut 2012;61:965–

966.

6. Corleto VD. Somatostatin and the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes

2010;17:63–68.

7. Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front

Neuroendocrinol 2013;34:228–252.

8. Urushidani T, Forte JG. Signal transduction and activation of acid secretion in the parietal cell. J

Membr Biol 1997;59:99–111.

9. Waldum HL, Brenna E, Kleveland PM, et al. Gastrin—physiological and pathophysiological role:

clinical consequences. Dig Dis 1995;13:25–38.

10. Quigley EM. Gastric and small intestinal motility in health and disease. Gastroenterol Clin North Am

1996;25:113–145.

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Chapter 45

Gastroduodenal Ulceration

Michael W. Mulholland

Key Points

1 Mucosal infection with Helicobacter pylori is the factor that contributes to ulcer pathogenesis in most

patients.

2 H. pylori virulence factors include vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A

(CagA).

3 As a group, patients with duodenal ulcers have an increased capacity for gastric acid secretion

relative to normal people.

4 Current treatment of peptic ulceration involves a combination of an antisecretory drug, usually a

proton pump inhibitor, with antibiotics.

5 Hemorrhage is the leading cause of death associated with peptic ulcer. Patients with recurrent

hemorrhage and elderly patients are at greatest risk of death.

6 For perforation, current therapy includes omental patch closure with postoperative anti–H. pylori

therapy. Minimally invasive approaches are becoming standard practice.

7 Major trauma accompanied by shock, sepsis, respiratory failure, hemorrhage, or multiorgan injury is

often accompanied by acute stress gastritis.

EPIDEMIOLOGY

Peptic ulceration remains a major public health problem worldwide. Worldwide prevalence of peptic

ulcer disease ranges from 0.1% to 4.7% with an overall incidence of 0.2% to 0.3%.1 With improving

public hygiene and effective treatment of Helicobacter pylori, most epidemiologic studies are now

reporting falling incidence rates. The surgical treatment of peptic ulcer has changed fundamentally. New

insights into disease pathogenesis, especially the realization that gastric infection has a role in most

cases of peptic ulceration, have been especially exciting. Antibiotics are now front-line antiulcer

therapy. A number of powerful antisecretory drugs have been introduced into clinical practice. Medical,

endoscopic, and surgical therapies are frequently integrated in the care of individual patients.

PATHOPHYSIOLOGY

1 The pathogenesis of peptic ulceration is complex and multifactorial but increasingly understood.

Approximately 75% of peptic ulcer cases are caused by H. pylori, with almost all other cases due to use

of nonsteroidal anti-inflammatory drugs (NSAIDs).2 Both NSAID use and H. pylori infection are

independent risk factors for development of peptic ulcer disease. The development of peptic ulceration

is often depicted as a balance between chronic inflammatory injury, acid–peptic secretion, and mucosal

defense, with the equilibrium shifted toward disease. Although acid–peptic secretion is crucial in the

development of ulcers, usually a defect in mucosal defense induced by bacterial infection also exists to

tip the balance away from health. Mucosal infection with H. pylori is the factor that contributes to ulcer

pathogenesis in most patients.

Helicobacter pylori

The relation between H. pylori infection and ulceration is inferential but overwhelmingly strong; a

causal relation between H. pylori infection and peptic ulceration has not been tested directly. Because H.

pylori infection is difficult to eradicate with certainty, and because of the potentially serious

consequences of infection, the intentional exposure of humans to the organism to establish such a

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relation is not justified.

Many lines of evidence establish H. pylori as a factor in the pathogenesis of duodenal ulceration:

H. pylori is the primary cause of chronic active gastritis, characterized by nonerosive inflammation of

the gastric mucosa. Antral gastritis is nearly always present histologically in patients with duodenal

ulcer, and H. pylori can be isolated from gastric mucosa in almost all cases.

Gastric metaplasia is extremely common in duodenal epithelium surrounding areas of ulceration. H.

pylori binds only to gastric-type epithelium, regardless of location; metaplastic gastric epithelium can

become colonized by H. pylori from gastric sources. Gastric metaplasia of the duodenal bulb is a

nonspecific response to damage and is the means by which antral gastritis with H. pylori is converted

to active chronic duodenitis.

Eradication of H. pylori with antimicrobials that have no effect on acid secretion leads to ulcer healing

rates superior to those seen with acid-suppressing agents.

Relapse of duodenal ulcer after antimicrobial therapy is preceded by reinfection of the gastric mucosa

by H. pylori.

In addition, half of patients evaluated for dyspepsia, but without ulceration, have histologic evidence

of mucosal bacterial infection. Furthermore, 20% of healthy volunteers harbor the bacteria; the

incidence of bacterial carriage in the healthy, asymptomatic population increases with age. The

occurrence of peptic ulcers in only a small proportion of people who carry the organism suggests that

other factors must also act to induce ulceration. The ability of H. pylori infection to induce alterations in

gastric acid secretion is a prerequisite for ulcer development in most patients.

H. pylori is the most common bacterial infection worldwide. H. pylori infection is usually acquired in

childhood and lasts lifelong in the absence of specific therapy. Epidemiologic studies suggest that H. pylori

infection occurs via person-to-person contact, usually among family members. Transmission is believed

to occur during a bout of gastroenteritis; the highest risk is associated with vomiting.

H. pylori is the only human bacterium to persistently infect the stomach. The organism is actually

somewhat fragile, being killed by exposure to high levels of oxygen and to the low pH found in the

acidic lumen of the stomach. To avoid the bactericidal activity of the stomach, the organism has evolved

mechanisms to move within the gastric environment, to adhere to gastric mucosa, and to protect itself

from the harmful effects of acid. Over 300 genes of H. pylori are regulated by acid.

H. pylori bacteria are spiral shaped with polar flagella. Most bacilli are free-swimming within the

mucous layer covering the gastric epithelium. The organisms orient according to a pH gradient, moving

away from the lower pH of the lumen toward the epithelium. The majority of organisms remain motile

within the mucous layer, but contact promotes adherence to epithelial cells, particularly in the region of

intercellular junctions. The products of more than 30 genes are expressed on the outer membrane of the

bacterium and function as adhesins to promote attachment to the gastric cells’ surface. The bestcharacterized adhesin binds to the Lewis blood group antigen b. Adhesion triggers the expression of

other bacterial genes, including bacterial virulence factors.

2 All strains of H. pylori cause persistent infection and all strains induce gastric inflammation. Yet,

only 15% of infected individuals develop peptic ulceration and only 1% develop gastric

adenocarcinoma. Differential expression of bacterial virulence factors is presumed to account for these

observations. Two virulence factors are best characterized: vacuolating cytotoxin A (VacA) and

cytotoxin-associated gene A (CagA) (Table 45-1).3

VacA is a pore-forming cytotoxin. VacA is expressed in all strains of H. pylori but is polymorphic with

marked variation in two regions. The VacA protein is 88 kD. Upon secretion from the bacterium, the

protein moves to the host cell membrane, where it forms a ring structure in the shape of a flower.4 This

ring complex inserts into the membrane of the host cell, creating a pore. VacA pores are permeable to

anions and small neutral molecules, including urea. Pore formation may be a mechanism by which the

organism obtains nutrients from gastric epithelial cells.

VacA also inserts into endosomal membranes, leading to osmotic swelling. VacA induces gastric cell

death through apoptosis. This action is thought to occur via pore formation in mitochondrial

membranes. VacA has been reported to interfere with immune T-cell activation and proliferation. This

activity may inhibit clearance of the organism by immune mechanisms.

The second major virulence factor in H. pylori is termed CagA.5,6 The CagA gene is part of a region of

DNA that is inserted into the genome of more virulent strains of H. pylori, termed a pathogenicity island.5

The genes in this island that are adjacent to the CagA gene encode proteins, which function as

microscopic needles for the transfer of bacterial products into host gastric cells. CagA is transferred to

host cells through this injection mechanism.

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Table 45-1 Helicobacter Pylori Virulence Factors

After CagA protein is transferred to host cells, it becomes phosphorylated on tyrosine residues by host

cell kinases. Phosphorylated CagA activates a number of cellular signaling pathways involved in cellular

polarity, cytoskeletal protein function, and cellular proliferation and differentiation. As a consequence,

infected gastric cells change shape and become more elongated. Apical junctions between cells become

disrupted, gaps develop between epithelial cells, and epithelial barrier function is lost. CagA protein

also stimulates transcription factors involved in regulation of cellular proliferation. Disturbance of

cellular function in favor of apoptosis affects epithelia restitution and may inhibit ulcer healing.

Acid-Secretory Status

3 The formation of duodenal ulcers depends on gastric secretion of acid and pepsin. As a group, patients

with duodenal ulcers have an increased capacity for gastric acid secretion relative to normal people

(Table 45-2). The maximal acid output of normal men is approximately 20 mEq/h in response to

intravenous histamine stimulation, whereas patients with duodenal ulcer secrete an average of

approximately 40 mEq/h. Considerable overlap exists between these two groups, and the values for

most people with duodenal ulcer fall within the normal range. The increase in acid secretion in some

patients with duodenal ulcer has been postulated to be due to an increase in the mass of parietal cells in

the acid-secreting gastric mucosa or to an increased sensitivity to circulating gastrin.

Groups of patients with duodenal ulcer demonstrate a prolonged and larger acid-secretory response to

a mixed meal than do groups of normal subjects. As with histamine-stimulated acid output, overlap

exists between patients with duodenal ulcer and normal subjects. Disturbances in gastric motility can

exacerbate meal-stimulated acid-secretory abnormalities.

Patients with duodenal ulcer have accelerated emptying of gastric contents, particularly liquids, after

a meal, and duodenal acidification fails to slow emptying appropriately. In such patients, the duodenal

mucosa can be exposed to low pH for prolonged periods relative to normal subjects.

ETIOLOGY

Table 45-2 Pathogenesis of Peptic Ulcer

Groups of patients with duodenal ulcer also demonstrate increased basal secretion of acid. Increased

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basal secretion can be demonstrated by nocturnal collection of gastric secretions.

Studies indicate that most of these secretory abnormalities are a direct consequence of H. pylori

infection. Paradoxically, the earliest stages of H. pylori infection are accompanied by a marked decrease

in gastric acid secretion. Acute antral gastritis is followed by fundal inflammation. Fundal inflammation

is associated with mucosal production of a number of cytokines, including interleukin (IL)-1β, IL-6, IL-8,

and tumor necrosis factor-α (TNF-α). IL-1β is a potent inhibitor of gastric acid secretion. Investigators

have postulated that acute reduction in gastric acid secretion facilitates further gastric colonization with

H. pylori. Acute hypochlorhydria resolves despite persistence of H. pylori and is followed by a state of

chronically increased acid secretion.

Basal and peak acid outputs are increased in patients with duodenal ulcer infected with H. pylori

relative to uninfected healthy volunteers. With eradication of H. pylori infection, basal acid output

returns to normal within 4 weeks, and peak acid output declines to the normal range by 6 months. Peak

acid output reflects parietal cell mass; the slow return to normal levels suggests that H. pylori infection

may stimulate increases in the parietal cell mass.

Abnormalities in acid secretion and parietal cell mass appear to be due to H. pylori–induced

hypergastrinemia.7 H. pylori–infected patients have increased basal serum gastrin levels, increased

gastrin responses to meal stimulation, and an augmented gastrin response to intravenous gastrinreleasing peptide. Eradication of H. pylori infection causes serum gastrin levels to return to baseline.

Gastric mucosal inflammatory cells and epithelial cells are activated by H. pylori infection to release

cytokines such as IL-8, interferon-γ, and TNF-α. These cytokines are stimulants of gastrin release from

cultured canine gastrin cells.

H. pylori expresses Nα-histamine methyltransferase activity. This enzyme produces Nαmethylhistamine, an abnormal analogue of histamine that can act as a gastric acid-secretory stimulant.

The concentration of somatostatin in the antral mucosa and the number of somatostatin-producing

cells in the antrum are diminished in H. pylori–infected patients. Treatment of H. pylori infection is

followed by increases in numbers of somatostatin cells and in mucosal somatostatin messenger RNA

levels. These observations suggest that alterations in mucosal somatostatin metabolism may also

contribute to the hypergastrinemia seen in H. pylori–infected patients by removing the inhibitory effects

that somatostatin exerts on gastrin release. Somatostatin release is also suppressed by Nαmethylhistamine.

Mucosal Defense against Peptic Injury

Gastric surface epithelial cells secrete mucus and bicarbonate, creating a pH gradient within the mucous

layer that is nearly neutral at the mucous cell surface, even when the lumen is highly acidic. Failure of

normal bicarbonate secretion locally would, in theory, result in exposure of surface epithelial cells to

the peptic activity of gastric secretions at low pH. Patients with duodenal ulcers have been

demonstrated to have significantly lower basal bicarbonate secretion in the proximal duodenum than

normal subjects. In addition, in response to a physiologically relevant amount of hydrochloric acid

instilled into the duodenal bulb, stimulated bicarbonate output was approximately 40% of the normal

response. Abnormalities in duodenal bicarbonate secretion normalize after elimination of H. pylori in

infected patients. These results suggest one mechanism by which ulceration could occur, even in

patients secreting normal amounts of acid.

Diminished mucosal prostaglandin production has also been proposed to exist in subsets of patients

with duodenal ulcer. Prostaglandins and prostaglandin analogues have been shown to exert

cytoprotective effects, to accelerate healing of established duodenal ulcers, and to decrease acid

secretion. In the duodenum, locally produced prostaglandins stimulate mucosal bicarbonate secretion. In

patients with active duodenal ulceration, gastric mucosal production of prostaglandin E2 and other

prostanoids has been shown to be diminished. An increase in prostanoid synthesis within the gastric

mucosa characterizes ulcer healing. Duodenal bicarbonate responses to prostaglandin E2 are impaired in

patients with duodenal ulcer.

Inflammatory responses to H. pylori infection are central to the pathogenesis of peptic ulceration.

While H. pylori infection always induces inflammation, the patterns of response are not uniform. Three

major patterns have been recognized.8,9 The most common pattern is a mild to moderate inflammation

of all regions of the stomach. This form is not associated with major alterations in gastric acidity and

most individuals are asymptomatic and do not develop peptic ulceration. Approximately 15% of infected

individuals develop an antral-predominant form of gastritis. These individuals exhibit an intense

inflammation limited to the antrum without involvement of the mucosa of the gastric corpus. Gastrin

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